An In Silico-Guided Approach for Assessing Herb-Drug Interaction Potential: A Case Study with Cudrania tricuspidata Leaf Extracts

Abstract

Cudrania tricuspidata leaf extracts have long been utilized as traditional oriental medicines across Asian countries like Korea, China, and Japan. These extracts are renowned for their therapeutic benefits in addressing inflammation, tumors, obesity, and diabetes, maintaining their status as a pivotal folk remedy. Given the rising trend of combining medicinal herbs with conventional medications, it is imperative to explore the potential herb-drug interactions. However, there is a dearth of research on evaluating the herb-drug interactions of C. tricuspidata leaf extracts. Also, the intricate chemical composition of medicinal herbs presents methodological hurdles in establishing causal relationships between their constituents and herb-drug interactions. To overcome these challenges, a combined in silico and in vitro workflow was developed and effectively applied to evaluate the potential herb-drug interaction of C. tricuspidata leaf extracts along with the associated chemical factors. In in vitro CYP inhibition assays, C. tricuspidata leaf extracts exhibited potent inhibition of CYP1A2 and CYP2C8, with quercetin, kaempferol, and their glycosides identified as the major constituents. In silico analysis based on the prediction tools (ADMETlab 2.0 and pkCSM) identified key contributors to CYP inhibition, quercetin and kaempferol. Additionally, molecular docking analysis validated the binding of ligands (quercetin and kaempferol) to proteins (CYP1A2 and CYP2C8). These findings suggest that C. tricuspidata leaf extracts could inhibit CYP1A2 and CYP2C8, aiding in understanding the herb-drug interaction potential of C. tricuspidata leaf extracts for safe clinical application. Furthermore, this approach can be broadly applied to study herb-drug interactions of various medicinal herbs, enhancing their therapeutic benefits and reducing adverse reactions by considering chemical profiles relevant to herb-drug interaction potential in herbal preparations.

Keywords

Cudrania tricuspidata - herb-drug interactions - cytochrome P450 - in silico - in vitro - quercetin - kaempferol - flavonoids - Moraceae

Publication History

Received: 22 April 2024

Accepted after revision: 09 July 2024

Accepted Manuscript online:
09 July 2024

Article published online:
06 August 2024

• References

• 1 Lee DH, Son YH, Jang JH, Lee SY, Kim HJ. The growth characteristics and the active compounds of Cudrania tricuspidata fruits in different cultivation environments in South Korea. Plants (Basel) 2023; 12: 2107
• 2 Xin LT, Yue SJ, Fan YC, Wu JS, Yan D, Guan HS, Wang CY. Cudrania tricuspidata: An updated review on ethnomedicine, phytochemistry and pharmacology. RSC Adv 2017; 7: 31807-31832
• 3 Ko W, Kim N, Lee H, Woo ER, Kim YC, Oh H, Lee DS. Anti-Inflammatory effects of compounds from Cudrania tricuspidata in HaCaT human keratinocytes. Int J Mol Sci 2021; 22: 7472
• 4 Lee BW, Lee JH, Lee ST, Lee HS, Lee WS, Jeong TS, Park KH. Antioxidant and cytotoxic activities of xanthones from Cudrania tricuspidata . Bioorg Med Chem Lett 2005; 15: 5548-5552
• 5 An RB, Sohn DH, Kim YC. Hepatoprotective compounds of the roots of Cudrania tricuspidata on tacrine-induced cytotoxicity in Hep G2 cells. Biol Pharm Bull 2006; 29: 838-840
• 6 Hiep NT, Kwon J, Kim DW, Hwang BY, Lee HJ, Mar W, Lee D. Isoflavones with neuroprotective activities from fruits of Cudrania tricuspidata . Phytochemistry 2015; 111: 141-148
• 7 World Health Organization (WHO). WHO traditional medicine strategy: 2014 – 2023. Accessed June 18, 2024 at: http://who.int/publications-detail-redirect/9789241506096
• 8 Lin AX, Chan G, Hu Y, Ouyang DF, Ung COL, Shi LW, Hu H. Internationalization of traditional Chinese medicine: Current international market, internationalization challenges and prospective suggestions. Chin Med 2018; 13: 9
• 9 Jahromi B, Pirvulescu I, Candido KD, Knezevic NN. Herbal medicine for pain management: Efficacy and drug interactions. Pharmaceutics 2021; 13: 251
• 10 Suroowan S, Abdallah HH, Mahomoodally MF. Herb-drug interactions and toxicity: Underscoring potential mechanisms and forecasting clinically relevant interactions induced by common phytoconstituents via data mining and computational approaches. Food Chem Toxicol 2021; 156: 112432
• 11 Awortwe C, Makiwane M, Reuter H, Muller C, Louw J, Rosenkranz B. Critical evaluation of causality assessment of herb–drug interactions in patients. Br J Clin Pharmacol 2018; 84: 679-693
• 12 Clairet AL, Boiteux-Jurain M, Curtit E, Jeannin M, Gérard B, Nerich V, Limat S. Interaction between phytotherapy and oral anticancer agents: Prospective study and literature review. Med Oncol 2019; 36: 45
• 13 Li XQ, Xing H, Qin ZF, Yang J, Wang PL, Zhang XJ, Yao ZH, Yao XS. Potential metabolism determinants and drug–drug interactions of a natural flavanone bavachinin. RSC Adv 2020; 10: 35141-35152
• 14 Xiong GL, Wu ZX, Yi JC, Fu L, Yang ZJ, Hsieh CY, Yin MZ, Zeng XX, Wu CK, Lu AP, Chen X, Hou TJ, Cao DS. ADMETlab 2.0: An integrated online platform for accurate and comprehensive predictions of ADMET properties. Nucleic Acids Res 2021; 49: W5-W14
• 15 Pires DEV, Blundell TL, Ascher DB. pkCSM: Predicting small-molecule pharmacokinetic and toxicity properties using graph-based signatures. J Med Chem 2015; 58: 4066-4072
• 16 Hakkola J, Hukkanen J, Turpeinen M, Pelkonen O. Inhibition and induction of CYP enzymes in humans: An update. Arch Toxicol 2020; 94: 3671-3722
• 17 Zhao MZ, Ma JS, Li M, Zhang YT, Jiang BX, Zhao XL, Huai C, Shen L, Zhang N, He L, Qin SY. Cytochrome P450 Enzymes and Drug Metabolism in Humans. Int J Mol Sci 2021; 22: 12808
• 18 Prakash C, Zuniga B, Song CS, Jiang S, Cropper J, Park S, Chatterjee B. Nuclear receptors in drug metabolism, drug response and drug interactions. Nucl Receptor Res 2015; 2: 101178
• 19 Sun DY, Lu J, Zhang YJ, Liu J, Liu ZJ, Yao BY, Guo YQ, Wang X. Characterization of a novel CYP1A2 knockout rat model constructed by CRISPR/Cas9. Drug Metab Dispos 2021; 49: 638-647
• 20 Vardhan S, Sahoo SK. In silico ADMET and molecular docking study on searching potential inhibitors from limonoids and triterpenoids for COVID-19. Comput Biol Med 2020; 124: 103936
• 21 Jia L, Gao H. Machine Learning for In Silico ADMETIn silico ADMETPrediction. In: Heifetz A. editor Artificial Intelligence in Drug Design. New York, NY: Springer US; 2022: 447-460
• 22 Morcoss MM, Abdelhafez EMN, Ibrahem RA, Abdel-Rahman HM, Abdel-Aziz M, Abou El-Ella DA. Design, synthesis, mechanistic studies and in silico ADME predictions of benzimidazole derivatives as novel antifungal agents. Bioorg Chem 2020; 101: 103956
• 23 Fan JY, Fu AL, Zhang L. Progress in molecular docking. Quant Biol 2019; 7: 83-89
• 24 Zou W, Shi BR, Zeng T, Zhang Y, Huang BL, Ouyang B, Cai Z, Liu MH. Drug transporters in the kidney: Perspectives on species differences, disease status, and molecular docking. Front Pharmacol 2021; 12: 746208
• 25 Song HP, Chen J, Hong JY, Hao HP, Qi LW, Lu J, Fu Y, Wu B, Yang H, Li P. A strategy for screening of high-quality enzyme inhibitors from herbal medicines based on ultrafiltration LC-MS and in silico molecular docking. Chem Commun 2015; 51: 1494-1497
• 26 Li J, Wu Y, Ma Y, Bai L, Li Q, Zhou XL, Xu PX, Li XR, Xue M. A UPLC-MS/MS method reveals the pharmacokinetics and metabolism characteristics of kaempferol in rats under hypoxia. Drug Metab Pharmacokinet 2022; 43: 100440
• 27 Xing XT, Kong MZ, Hou QY, Li JQ, Qian W, Chen XJ, Li HH, Yang CQ. Effects of ginkgo leaf tablet on the pharmacokinetics of rosiglitazone in rats and its potential mechanism. Pharm Biol 2022; 60: 1190-1197
• 28 Zhang Y, Liu YN, Xie SL, Xu XG, Xu RA. Evaluation of the inhibitory effect of quercetin on the pharmacokinetics of tucatinib in rats by a novel UPLC–MS/MS assay. Pharm Biol 2022; 60: 621-626
• 29 Cassidy A, Minihane AM. The role of metabolism (and the microbiome) in defining the clinical efficacy of dietary flavonoids. Am J Clin Nutr 2017; 105: 10-22
• 30 Kim DH, Lee S, Chung YW, Kim BM, Kim H, Kim K, Yang KM. Antiobesity and antidiabetes effects of a Cudrania tricuspidata hydrophilic extract presenting PTP1B inhibitory potential. Biomed Res Int 2016; 2016: 8432759
• 31 Kim OK, Nam DE, Jun W, Lee J. Cudrania tricuspidata water extract improved obesity-induced hepatic insulin resistance in db/db mice by suppressing ER stress and inflammation. Food Nutr Res 2015; 59: 29165
• 32 Daily EB, Aquilante CL. Cytochrome P450 2C8 pharmacogenetics: A review of clinical studies. Pharmacogenomics 2009; 10: 1489-1510
• 33 Rehman SU, Kim IS, Choi MS, Kim SH, Zhang YH, Yoo HH. Time-dependent Inhibition of CYP2C8 and CYP2C19 by Hedera helix extracts, a traditional respiratory herbal medicine. Molecules 2017; 22: 1241
• 34 Seo JI, Yu JS, Zhang Y, Yoo HH. Evaluating flavonoids as potential aromatase inhibitors for breast cancer treatment: In vitro studies and in silico predictions. Chem Biol Interact 2024; 392: 110927